PROJECT SUMMARY/ABSTRACT Research: Contrary to children in the US with sickle cell anemia (SCA) who develop dysfunctional, atrophic spleens by 5 years old, children with SCA in sub-Saharan Africa often have splenomegaly, but its functional status and clinical consequences are unknown. The long-term goal of this research is to understand the etiology, pathophysiology, and clinical consequences of splenomegaly in children with SCA in sub-Saharan Africa. The goal of this proposal is to investigate the etiology and clinical effects of splenomegaly both before and after hydroxyurea treatment in a large cohort of children with SCA, enrolled in a prospective treatment trial (SPHERE, NCT03948867). The candidate's ancillary trial will collect serial measurements of both splenic volume (3-dimensional ultrasound) and splenic function (Howell Jolly bodies, pitted red blood cells, and specific viral serologies) in both the observation and the treatment groups of the SPHERE cohort and address these specific aims: 1) identify factors associated with splenomegaly prior to treatment and correlate anatomy (3-dimensional volume) with physiology (filtrative and immunological functions) and 2) investigate changes in splenic volume and function during hydroxyurea treatment as well as laboratory and clinical effects of hydroxyurea compared to untreated participants. These aims will test the following hypotheses: 1A) baseline splenomegaly will be present in 10-20% and associated with alpha thalassemia and previous malaria infections; 1B) pre-treatment splenic size will not correlate with function; 2A) incidence of splenomegaly will double in children receiving hydroxyurea compared to untreated children and be predicted by pre-treatment splenic volume, HbF response, and new malarial infections; 2B) splenomegaly with hydroxyurea treatment will be associated with improved splenic filtrative function and preserved immunological function. Career Development Plan: Dr. Smart's long-term goal is to become an independent investigator focused on improving outcomes for persons with sickle cell disease in the US and globally. He will pursue the following objectives during his K23 training: 1) obtain mentorship in the implementation of rigorous clinical trials in low- resource settings by conducting a prospective clinical trial among children with SCA in Tanzania; 2) understand the significance of splenic dysfunction in SCA through educational seminars and laboratory experience that includes quantitative and qualitative assessments of spleen anatomy and physiology; and 3) gain experience in clinical trial design and advanced statistical methods through coursework and data analysis. Environment: The proposed research will be conducted at Cincinnati Children's Hospital Medical Center (Cincinnati, Ohio) and Bugando Medical Centre (Mwanza, Tanzania) who have a longstanding partnership that provides a strong collaborative environment with infrastructure for clinical and translational research, outstanding mentorship, and an excellent team of collaborators with expertise in sickle cell disease, immunology, hydroxyurea therapy, biostatistics, and clinical trials in low-resource settings.